There are several metabolic diseases of human and animal metabolism, eg., obesity and severe weight loss that relate to energy imbalance--where caloric intake versus energy expenditure--is imbalanced. Obesity, which can be defined as a body weight more than 20% in excess of the ideal body weight, is a major health problem in Western affluent societies. It is associated with an increased risk for cardiovascular disease, hypertension, diabetes, hyperlipidaemia and an increased mortality rate. Obesity is the result of a positive energy balance, as a consequence of an increased ratio of caloric intake to energy expenditure. The molecular factors regulating food intake and body weight balance are incompletely understood. Five single-gene mutations resulting in obesity have been described in mice, implicating genetic factors in the etiology of obesity. (Friedman, J. M., and Leibel, R. L. Cell 69: 217-220 (1990)). In the ob mouse a single gene mutation, obese, results in profound obesity, which is accompanied by diabetes (Friedman, J. M., et. al. Genomics 11: 1054-1062 (1991)). Cross-circulation experiments have suggested that the ob mice are deficient of a blood-borne factor regulating nutrient intake and energy metabolism (Coleman, D. L. Diabetologia 14: 141-148 (1978)). Using positional cloning technologies, the mouse ob gene, and subsequently its human homologue, have been recently cloned (Zhang, Y., et. al., Nature 372: 425-432 (1994)). Daily intraperitoneal injections of either mouse or human recombinant OB protein reduced the body weight of obese mice ob/ob by 30% after 2 weeks of injection. The protein reduced food intake and increased energy expenditure in the ob/ob mice (Halaas et. al., Science 269: 543-546 (1995)).
Cachexia on the other hand is characterized by severe weight loss and imbalanced energy expenditure, examples being patients with cancer or HIV infections.
The creatine kinase/creatine phosphate system is an energy generating system operative predominantly in the brain, muscle, heart, retina, adipose tissue and the kidney (Walliman et. al., Biochem. J. 281: 21-40 (1992)). The components of the system include the enzyme creatine kinase (CK), the substrates creatine (Cr), creatine phosphate (CrP), ATP,ADP, and the creatine transporter. The enzyme catalyses reversibly the transfer of a phosphoryl group from CrP to ADP to generate ATP which is the main source of energy in the cell. This system represents the most efficient way to generate energy upon rapid demand. The creatine kinase isoenzymes are found to be localized at sites where rapid rate of ATP replenishment is needed such as around ion channels and ATPase pumps. Some of the functions associated with this system include efficient regeneration of energy in the form of ATP in cells with fluctuating and high energy demand, energy transport to different parts of the cell, phosphoryl transfer activity, ion transport regulation, and involvement in signal transduction pathways.
The substrate Cr is a compound which is naturally occurring and is found in mammalian brain, skeletal muscle, retina, adipose tissue and the heart. It's phosphorylated form CrP is also found in the same organs and is the product of the CK reaction. Both compounds can be easily synthesized and are believed to be non toxic to man. A series of creatine analogues have also been synthesized and used as probes to study the active site of the enzyme. Kaddurah-Daouk et al. (WO 92/08456 published May 29, 1992 and WO 90/09192, published Aug. 23, 1990; U.S. Pat. No. 5,321,030; and U.S. Pat. No. 5,324,731) described methods for inhibiting growth, transformation, or metastasis of mammalian cells using related compounds. Examples of such compounds include cyclocreatine, homocyclocreatine and beta guanidino propionic acid. These same inventors have also demonstrated the efficacy of such compounds for combating viral infections (U.S. Pat. No. 5,321,030). Elgebaly in U.S. Pat. No. 5,091,404 discloses the use of cyclocreatine for restoring functionality in muscle tissue. Cohn in PCT publication No. WO 94/16687 describes a method for inhibiting the growth of several tumors using creatine and related compounds.
It is an object of the present invention to provide methods for treatment of metabolic diseases that relate to deregulated body weight by administering to an afflicted individual an amount of a compound or compounds which modulate one or more of the structural or functional components of the creatine kinase/creatine phosphate system sufficient to prevent, reduce or ameliorate the symptoms of the disease. These compounds are collectively referred to as "creatine compounds."